Radiodiagnostic agents and radiopharmaceutical agents play a decisive role in the diagnosis and combating of cancers. The tendency of many cancers to form metastases places high requirements on the efficiency specifically of radiodiagnostic agents as a serious tool for early detection of all metastases. This early detection of affected tissues in the body has a significant influence on the indicated therapy process. As a special example in this case, the extremely aggressive metastasis formation in malignant melanomas can be mentioned.
The early location of metastases is of special importance for the treatment of melanoma that grows aggressively. The lesions that are identified by means of computer tomography (x-ray radiation) generally require an invasive histological examination, however.
In this connection, nuclear-medicine research has developed a number of compounds that emit positrons and photons that accumulate after intravenous injection because of their property as metabolic substrate or bond to tumor-specific target structures in the primary tumor and in evacuated melanoma metastases. The graphic visualization of the activity distribution and the possible concentrations in the tumors are then performed with a positron-emission-tomography (PET) camera or a gamma camera, associated anatomically, evaluated and documented. As a gold standard of radioactive diagnostic agents, [F-18]2-fluoro-deoxyglucose (FDG) is now used for PET diagnosis (D. Delbeke et al. J. Nucl. Med. 40: 591-603 (1999); D. J. Macfarlane et al. J. Clin. Oncol. 16: 1770-1776 (1998); J. Ruhlmann et al. J. Nucl. Med. 40: 20P(1999). The absence of a suitable therapeutically relevant isotope pair represents a general drawback of [F-18]-labeled compounds. [F-18]2-Fluoro-deoxyglucose (FDG) can therefore be used exclusively for diagnosis.
It is specifically in the treatment of melanomas, because of early and aggressive metastasizing behavior, that only a very short survival period can be expected, especially in the case of patients in stages III and IV (see NIH Consensus Development Panel on Early Diagnosis and Treatment of Early Melanoma, J. Am. Med. Assoc. 268: 1314-1319 (1992); D. S. Rigel et al. CA Cancer J. Clin. 50: 215-236 (2000)). All approaches to a treatment with chemotherapeutic agents (Dacarbazin® by itself or Dartmouth protocol, etc.), immunotherapy (Interferon-Alpha, etc.) and gene therapy are not very successful to date. Operative removal of the metastases is the means of choice, but it often cannot be applied in the case of attacks of several organs. The use of a specific marker for melanomas, which can be provided with a diagnostic/therapeutic isotope pair and can be used for systemic treatment of multiple metastases, is therefore of great interest. Such isotope pairs were for example I-123 or I-124 (diagnosis) and I-125 or I-131 (therapy). In addition, In-111/Y-86/Tc-99m (diagnosis) and Y-90/Re-186/Re-188 (therapy) can be mentioned.
The discovery that various radioiodinated benzamides have an affinity relative to melanocytes resulted in the development of various N-(2-dialkylaminoalkyl)-4-iodobenzamide derivatives (J. M. Michelot et al.: J. Nucl. Med. 32: 17573-1580 (1991) and U.S. Pat. No. 5,190,741), which were also tested clinically for the diagnosis of melanoma in a Phase II Study (J. M. Michelot et al.: J. Nucl. Med. 34: 1260-1266 (1993)). The described results show considerably improved absolute images relative to the use of simple radiolabeled amino acids such as iodo-thyrosine (for example, G. Kloss et al. Eur. J. Nucl. Med. 4: 179-186 (1979)). Compared to radioiodinated antibodies, more advantageous melanoma background properties would be achieved (cf: S. M. Larson et al. J. Nucl. Med. 32: 2887-291 (1991); G. L. Buraggi et al. Cancer Res. 45: 3378-3385 (1985)). Nevertheless, the latter with a 123-I-labeled compound for clinical use has disadvantageous properties especially with respect to the therapeutic application. The retardation in the tumor and the maximum concentration should be improved.
In addition, high background concentration of the compound leads to low-contrast visualization primarily in internal organs compared to extremities or to the head.
EP 0 317 873 B1 describes additional radioiodinated benzamides and their use as radiodiagnostic agents, thus, for example, 123-I-(S)-N-[(1-ethyl-2-pyrrolidinylmethyl]-5-iodo-2-methoxybenzamide.
By the introduction of polar groups on the phenyl radicals of the radiohalogenated benzamide derivatives, it has been possible to reduce these drawbacks (B. Bubeck, M. Eisenhut, A. Mohammed, C. Nicholl DE 195 19 508.6-41), but the problem continues to exist that the cited radioiodinated benzamides should be improved for therapeutic applications with respect to higher tumor accumulation and extended retardation.
The attempt to achieve the radiolabeling of benzamide derivatives by means of Tc-99m radio metal labeling and thus to use an economical isotope that is available through a generator resulted in compounds with considerably reduced melanoma accumulation (U. Titsch et al. J. Labelled Compds. Radiopharm. 40: 416-418 (1997); P. Auzeloux et al. J. Med. Chem. 43: 190-198 (2000). The substitution of the aromatic ring in the benzamide derivatives by a quadratic-pyramidal “3+1-” or amine-amide-dithiol-metal core while preserving the diethylamino-ethylene fragment resulted in a considerable improvement in the melanoma image (M. Friebe et al. J. Med. Chem. 43: 2745-2752 (2000); M. Friebe et al. J. Med. Chem. 44: 3132-3140 (2001); M. Eisenhut et al. J. Med. Chem. 45: 5802-5805 (2002)), but does not come up to the standard of the benzamide derivatives that are described below.
In J. Med. Chem. 2000, 43(21), 3913-22, DE. 196 32 052 and Eisenhut et al. described, i.a., two benzamides named “BA40” and “BA42” with extraordinarily high concentration in the C57BL6-B16/F1 mouse model. In their publication, Eisenhut et al. describe the liver concentration of BA42, as the “best” compound, as the possible drawback of this compound especially for therapeutic applications. Another critical point is the blood accumulation of this compound with respect to the red bone marrow, which can result in limitations in the application for radiotherapy.
It is therefore an object of this invention to provide a radiopharmaceutical agent for the diagnosis and treatment of tumors, especially melanomas, whose affinity for tumor tissue is sufficiently high and that ensures a maximum “therapeutic window” (amount of radioactivity in tumor versus non-tumor) by sufficiently quick elimination from the remainder of the body. In this case, special attention is to be placed on tumor concentration and retardation, liver concentration and blood accumulation.
This object is achieved according to the invention by the provision of benzamide derivatives that have similar structural elements to the known, highly specific and highly sensitive radiohalogenated benzamide derivatives and can be used as complex ligands for transition metals. These radiohalogenated benzamide derivatives according to the invention have general formula (I)
in which radicals X1 to X5, independently of one another, in each case represent a halogen, hydrogen, a radical of formula —NR1R2, an ether of formula —O—R3, a branched or unbranched C1-C10 alkyl group, e.g. C1, C2, C3, C4, C5, C6, C7, C8, C9, or C10 alkyl group, a branched or unbranched C2-C10 alkenyl group, e.g. C1, C2, C3, C4, C5, C6, C7, C8, C9, or C10 alkenyl group, or an aryl or heteroaryl group that optionally can be substituted in each case by halogen or low alkoxy, whereby two adjacent radicals X1 to X5 can form a 5- to 7-membered ring, whereby one or more carbon atoms of the ring can be replaced by heteroatoms such as N, O or S, and radical X6 is an oxygen or ═NH, and
radicals X7 and X8 can be the same or different and are hydrogen, substituted or unsubstituted C1-12 alkyl, e.g. C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11 or C12 alkyl, in particular methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, substituted or unsubstituted C2-12 alkenyl, e.g. C2, C3, C4, C5, C6, C7, C8, C9, C10, C11 or C12 alkenyl, in particular ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, substituted or unsubstituted C3-6 cycloalkyl, e.g. C3, C4, C5, or C6 cycloalkyl, substituted or unsubstituted C3-6 cycloalkenyl, e.g. C3, C4, C5, or C6 cycloalkenyl, substituted or unsubstituted C2-6 carbalkoxyalkyl, e.g. C2, C3, C4, C5, or C6 carbalkoxyalkyl, substituted or unsubstituted C2-6 carbalkoxyalkenyl, e.g. C2, C3, C4, C5, or C6 carbalkoxyalkenyl, —C1-12alkylNR8R9, e.g. C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11 or C12 alkylNR8R9 in particular -methylNR8R9, -ethylNR8R9, -propylNR8R9, or substituted or unsubstituted C6-12 aryl or heteroaryl; in each case optionally substituted in one or more places by —OR4, —COOR5, —CONR6R7, cyano, halogen or —NR8R9; or X7 and X8 together form a 5- to 7-membered ring, whereby one or more carbons of the ring can be replaced by heteroatoms, such as N, O or S, whereby                R1 and R2 are the same or different and are hydrogen, C1-12 alkyl, e.g. C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, or C12 alkyl, in particular methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, C2-12 alkenyl, e.g. C2, C3, C4, C5, C6, C7, C8, C9, C10, C11 or C12 alkenyl, in particular ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, C3-6 cycloalkyl, e.g. C3, C4, C5, or C6 cycloalkyl, C3-6 cycloalkenyl, e.g. C3, C4, C5, or C6 cycloalkenyl, C2-6 carboxyalkyl, e.g. C2, C3, C4, C5, or C6 carbalkoxyalkyl, C2-6 carboxyalkenyl, e.g. C2, C3, C4, C5, or C6 carbalkoxyalkenyl, C6-12 arylsulfonyl, e.g. C6, C7, C8, C9, C10, C11, or C12 arylsulfonyl, carboxyaryl, in particular C7-13 carboxyaryl, e.g. C7, C8, C9, C10, C11, C12, or C13 carboxyaryl, or carboxyheteroaryl, in particular C7-13 carboxyheteroaryl, e.g. C7, C8, C9, C10, C11, C12 or C13 carboxyheteroaryl, wherein the carboxyheteroaryl preferably comprises 1, 2, 3, 4, 5 or 6 hetero atoms selected from the group S, N, or O; in each case optionally substituted in one or more places, e.g. 1, 2, 3, 4 or 5 substitutions, by preferably aryl, heteroaryl, OR4, COOR5, CONR6R7, cyano, halogen, NR8R9, or two substituents, preferably adjacent substituents taken together form a 3, 4, 5, 6, 7 or 8 membered ring optionally with 1, 2, 3, or 4 hetero atoms, e.g. selected from O, S, or N, provided that R1 and R2 cannot simultaneously be hydrogen,        R3 is hydrogen, C6-12 aryl, heteroaryl, C1-10 alkyl, e.g. C1, C2, C3, C4, C5, C6, C7, C8, C9, or C10, alkyl, in particular methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, pentyl, hexyl, heptyl, C2-10 alkenyl, e.g. C2, C3, C4, C5, C6, C7, C8, C9, or C10, alkenyl, in particular ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, C2-10 alkynyl, e.g. C2, C3, C4, C5, C6, C7, C8, C9, or C10 alkynyl, in particular ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, C3-6 cycloalkyl, e.g. C3, C4, C5, or C6 cycloalkyl, C3-6 cycloalkenyl, e.g. C3, C4, C5, or C6 cycloalkenyl; in each case optionally substituted in one or more places preferably by OR4, COOR5, CONR6R7 (whereby polyethers, such as, e.g., C—O—C—C—O—C—R, are possible, since an O-alkyl group can be substituted by O-alkyl), cyano, halogen or NR8R9,        R4 and R5 are the same or different and are hydrogen, C1-12 alkyl, e.g. C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11 or C12 alkyl, in particular methyl, ethyl, propyl, butyl, pentyl, hekyl, heptyl, C2-12 alkenyl, e.g. C2, C3, C4, C5, C6, C7, C8, C9, C10, C11 or C12 alkenyl, in particular ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, C3-6 cycloalkyl, e.g. C3, C4, C5, or C6 cycloalkenyl, C3-6 cycloalkenyl, e.g. C3, C4, C5, or C6 cycloalkenyl; in each case optionally substituted in one or more places preferably by aryl, heteroaryl, OR10, COOR11, CONR6R7, cyano, halogen or NR8R9,        R6, R7, R8 and R9 are the same or different and are hydrogen, C1-12 alkyl, e.g. C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11 or C12 alkyl, in particular methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, pentyl, hexyl, heptyl, C2-12alkenyl, e.g. C2, C3, C4, C5, C6, C7, C8, C9, C10, C11 or C12 alkenyl, in particular ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, C3-6 cycloalkyl, e.g. C3, C4, C5, or C6 cycloalkenyl, C3-6 cycloalkenyl, e.g. C3, C4, C5, or C6 cycloalkenyl, in each case optionally substituted in one or more places by preferably OR4, or R6 and R7 or R8 and R9 in each case together form a 5- to 7-membered ring, whereby one or more carbons of the ring can be replaced by heteroatoms such as N, O or S, and        R10, R11 are the same or different and can be hydrogen, C1-12 alkyl, e.g. C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11 or C12 alkyl, in particular methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, pentyl, hexyl, heptyl, C2-12 alkenyl, e.g. C2, C3, C4, C5, C6, C7, C8, C9, C10, C11 or C12 alkenyl, in particular ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, C3-6 cycloalkyl, e.g. C3, C4, C5, or C6 cycloalkenyl, or C3-6 cycloalkenyl, e.g. C3, C4, C5, or C6 cycloalkenyl; which optionally can be substituted in each case in one or more places preferably by aryl, heteroaryl, OR4, COOR5, CONR6R7, cyano, halogen, or NR8R9,        
provided that
at least one of radicals X1 to X5, preferably X4 is a radioactive halogen,
at least one of radicals X1 to X5, preferably X1 is an ether —O—R3,
at least one of radicals X1 to X5, preferably X3 is a radical of formula —NR1R2, in which either R1 or R2 is a substituted or unsubstituted radical carboxyalkyl, in particular C2-6 carboxyalkyl, e.g. C2, C3, C4, C5 or C6 carboxyalkyl, carboxyalkenyl, in particular C2-6 carboxyalkenyl, e.g. C2, C3, C4, C5 or C6 carboxyalkenyl, carboxy aryl, in particular C7-13 carboxyaryl, e.g. C7, C8, C9, C10, C11, C12 or C13 carboxyaryl, or carboxyheteroaryl, in particular C7-C13 carboxy heteroaryl, e.g. C7, C8, C9, C10, C11, C12 or C13 carboxy heteroaryl; in each case optionally substituted in one or more places, e.g. 1, 2, 3, 4 or 5 substitutions, preferably by aryl, heteroaryl, OR4, COOR5, CONR6R7, cyano, halogen, NR8R9, or two substituents, preferably adjacent substituents taken together form a 3, 4, 5, 6, 7 or 8 membered ring optionally with 1, 2, 3, or 4 hetero atoms, e.g. selected from O, S, or N; preferably a carboxyalkyl, in particular C2-6 carboxyalkyl or carboxyaryl, in particular C7-13 carboxyaryl; in each case optionally substituted with one or more substituents from the group of halogen, e.g. F, Cl, Br or I, or —O—R4 or two substituents, preferably adjacent substituents, taken together from a 3, 4, 5, 6, 7 or 8 membered ring, optionally with 1, 2, 3 or 4 hetero atoms, e.g. Q, N, or S; more preferably substituted or unsubstituted C7 carboxyaryl, e.g. benzo-carbonyl, in particular halogen-benzo carbonyl, e.g. 1-fluoro-benzo-4-carbonyl, or 1-chloro-benzo-4-carbonyl, alkoxy-benzo-carbonyl, e.g. 1-methoxy-benzo-4-carbonyl, benzo-carbonyl or benzo-[1,3]dioxole-5-carbonyl; and that
if X1 is methoxy and X6 is O, X8 is hydrogen and X7 is NH(CH2)2Net2, and X4 means I131, X3 is not NHAc,
and physiologically compatible salts thereof.
Especially in reference to the therapeutic use of the compounds according to the invention, it has been shown that the blood accumulation of the compounds may be a critical point. It is very important that the compound which is labeled with the radio-active isotope is excreted from the blood as fast as possible. The compounds according to the invention and especially the compounds BA52 (see Formula (IIa)) or BA91; BA 93; BA95 and BA100 (Formula IIb-e), respectively show, surprisingly enough, considerably less blood accumulation than the closest prior art (compound of Eisenhut et al. with NH—Ac as substitution in the ring). This reduced blood concentration is advantageous with respect to the bone marrow toxicity.
In addition, the liver kinetics of the compounds according to the invention is much better than the liver kinetics of the most similar compound in the prior art. In particular, the final result was very surprising. It had been expected that the compounds according to the invention and in particular BA52 are more lipophilic by the substitution, and thus have a stronger protein bond (higher and longer accumulation in the blood) and, in addition, are metabolized more greatly via the liver. Compound 52 indeed has a higher lipophilicity but does advantageously not fulfill this expectation.
Another drawback of the most similar compounds of the prior art is that the compounds of Eisenhut et al. dehalogenate more quickly in the body than the compounds according to the invention. This is shown by the fact that in the compound according to the invention, the thyroid gland accumulation, produced by iodine released from the compound (the intact compound-does not accumulate in the thyroid gland tissue) is lower.
Surprisingly enough, compounds according to the invention, in particular BA52, BA 93, BA95 and BA 100 show an extended retardation in the melanoma tissue, which should mean an enlargement of the therapeutic window in the patient in connection with the previously named properties. The retardation over an extended period of time leads to an enhanced tumor dose. Therefore, the extended retardation in the melanoma tissue is more important than the initial tumor uptake (after 1 h).
In terms of structure, the compounds according to the invention are distinguished by the substitution in the aromatic amino group by carboxy alkyl, carboxy alkenyl, carboxy aromatic or carboxy heteroaromatic compounds with the formation of an amide bond.
As mentioned above, Eisenhut et al. have produced, i.e. two benzamides (BA40) and (BA42) which show extraordinarily high concentration in the C57BL6-B16/F1 mouse model. The tumor concentration of the compound BA52 according to the invention is comparable in this model, but the retention of BA52 in the tumor is considerably longer. This observation is even more striking in the NMRI-SK-Mel3 human xenograft mouse model. BA 40 is completely washed out of the tumor after 72 hours. In contrast thereto, BA 52 is still accumulated with at least 13% of the injected dose per gram tissue of the tumor after 96 hours.
In their publication, Eisenhut et al. describe the liver concentration of BA42, which is considered the “best” compound, as a possible drawback of this compound especially for therapeutic applications. The liver concentration of the substances according to the invention, in particular BA52, BA 91, BA93, BA95 and BA100, e.g., after 6 and 24 hours, is considerably lower (see Table 1). It is of importance that the compounds according to the present invention are excreted from the liver considerably faster than BA40 and BA42 although the initial accumulation in the liver is comparable. Another critical point is the blood accumulation of this compound, which can result in limitations in the application for radiotherapy. The BA52 according to the invention also shows here a considerably lower blood accumulation after 6 and 24 hours, respectively, (see Table 1) which leads to a remarkably lower radio-active dose to the bone marrow (lower side effects).
In addition, the radioisotope I-131 seems to be more stable in the compounds according to the invention and in particular bonded to BA52, BA91, BA93, BA95 and BA100. The thyroid gland accumulation of BA40 and BA42, an indication of dehalogenation in vivo, is increased by a factor of 10-15 compared to the compounds according to the invention.
The fact that despite higher lipophilicity, BA52 shows a lower blood accumulation in the mouse model (Table 1) is also advantageous. This was not predictable because of the usually higher blood plasma binding of more lipophilic substances. Also, more lipophilic substances are more likely metabolized by the liver such that a lower accumulation was not to be expected after 5 or 24 hours.
TABLE 1Tissue Concentration of Radioiodinated Benzamidesin the C57BL6-B16/F1 Mouse Model, n = 3Comparison SubstanceComparison SubstanceBA40′BA42′BA52Organ1 hour6 hours24 hours1 hour6 hours24 hours1 hour5 hours24 hoursTumor16.61*16.48 8.0221.87 23.32 16.06 14.8322.69 18.82 Blood2.321.860.193.302.560.21 1.460.690.05Liver11.32 9.614.548.039.863.7219.116.530.49BA91BA93BA95BA100Organ1 h6 h24 h1 h6 h24 h1 h5 h24 h1 h6 h24 hTumor9.6816.7213.8310.7321.6723.4617.4514.8329.6925.5128.1031.66Blood1.060.970.221.300.820.221.260.760.071.210.700.07Liver12.683.630.7613.715.811.1816.358.540.7515.494.640.76*% Injected Dose (ID)/g of Tissue
'Value from Eisenhut et al. J. Med. Chem. 2000, 43(21), 3913-22
Based on this organ distribution data in mice, dosimetry calculations were conducted. To this end, the “Medical Internal Radiation Dose” (MIRD) process was used (M. G. Stabin et al. J Nucl Med, 37: 538-546 (1996); R. Loevinger et al. Society of Nuclear Medicine, 1988, NY; J. A. Siegel et al. J. Nucl Med 35: 152-156 (1994); J. A. Siegel et al. J Nucl Med 40: 37S-61S (1999); G. Sgouros et al. J Nucl Med 34: 689-694 (1993); M. S. Muthuswamy et al. J Nucl Med 39: 1243-1247 (1998)). This process is based on a spherical model and calculates the radiation dose deposited in the tumor and the organs of the corresponding species as a function of the radioisotope that is used, the distribution of the compound in the body and the amount of radioactive compound administered (Table 2). Thus, estimates can be conducted for the “therapeutic window” of the compound as well as regarding expected side effects. A high dose value (mGy/MBq) in the tumor is advantageous while as low a value as possible for blood and organs produces a low radiation dose (side effect). Since the blood and organ dose determine the maximum dose that can be administered, compounds with low organ/blood doses and high tumor dose have the larger “therapeutic window.”
TABLE 2Dose quotient mGy/MBq for benzamide derivatives. Calculatedfor defined organs based on tumor and organ distribution experimentsin the syngenic C5BL6-B16 mouse tumor model. MIRDOSE 3.1, 1995,Stabin et al. was used for calculation. The areas under thecurve (residence times) on which the calculation is based werecalculated with SigmaPlot 8.02, SPSF, Inc.ComparisonComparisonSubstanceSubstanceBA40′BA42′BA52Dose/OrganmGy/MBqmGy/MBqmGy/mBqTumor (1 g)50712564870Blood35474Bone marrow13171Liver33232492
'Tumor and organ distribution data were taken from Eisenhut et al. J. Med. Chem. 2000, 43(21), 3913-22. The organ weights were normalized to standard mouse values.
According to the invention, a radiohalogenated benzamide derivative of this invention is preferred, whereby the halogen isotope is selected from F-18, Br-76, I-123, I-124, I-125, I-131 and At-211.
Further preferred is a radiohalogenated benzamide derivative of this invention, whereby the halogen isotope [I-131] is iodine, whose specific activity is between 10 mCi/mg and 1500 mCi/mg (non HPLC purified), preferably between 100 mCi/mg and 800 mCi/mg (non HPLC purified). If the compound is purified by HPLC or alike methods, the specific radioactivity will be determined by the specific activity of the isotope batch used and will be higher. Processes for determination of the specific activity are known to one skilled in the art and can be taken from relevant textbooks and/or scientific publications, such as, e.g., Wessels, B. W., Meares, C. F. Physical and Chemical Properties of Radionuclide Therapy. Semin kadiat Oncol. 2000 April; 10(2): 115-22, and the references cited therein.
Still more preferred is a radiohalogenated benzamide derivative of this invention, whereby radical X6 is an oxygen. As an alternative, radical X6 can be an ═NH group.
Also more preferred is a radiohalogenated benzamide derivative of this invention, whereby one of radicals X7 and X8 is a hydrogen.
Also more preferred is a radiohalogenated benzamide derivative of this invention, whereby one of radicals X7 and X8 is a hydrogen, while the other radical X7 or X8 is C1-C12 alkyl, substituted with an amine —NR8R9. It is particularly preferred that, if one of the radicals X7 and X8 is hydrogen that the other radical X7 or X8 is C2, C3 or C4 alkyl, substituted, preferably terminally with an amine —NR8R9, e.g. —CH2NR8R9, —CH2CH2NR8R9, —CH2CH2CH2NR8R9.
Even more preferred is a radiohalogenated benzamide derivative of this invention, whereby R8 and R9 are C2H5 or form a 5- or 6-membered ring, whereby one or more carbon atoms of the ring can be replaced by heteroatoms, such as N, O or S. R8 and R9 preferably have this preferred meaning when one of radicals X7 and X8 is hydrogen and the other radical X7 or X8 is C2, C3 or C4 alkyl, substituted, preferably terminally with an amine —N8R9, e.g. —CH2NR8R9, —CH2CH2NR8R9, —CH2CH2CH2NR8R9. In this context R8 and R9 preferably have the meaning substituted or unsubstituted methyl, ethyl, propyl or butyl.
Still more preferred is a radiohalogenated benzamide derivative of this invention, whereby one of radicals X1 to X5 represents a radical —NR1R2.
Also more preferred is a radiohalogenated benzamide derivative of this invention, whereby R1 is a carboxyaryl group, and R2 is a hydrogen. Still more preferred is a radiohalogenated benzamide derivative of this invention, whereby R1 is a C2-C6 carboxyalkyl or C2-C6 carboxyalkenyl, and R2 is a hydrogen. Especially preferred are arylcarboxyl substituents on R1.
Still more preferred is a radiohalogenated benzamide derivative of this invention, whereby X1 is selected from —O—R3, in particular from an —CH3 group, an —O—C2H5 group, an —O—C2H5O—CH3 group or an —O—C2H5—OH group.
A further preferred radio halogenated benzamide derivative of this invention, whereby X3 is a radical of formula —NR1R2 in which R1 or R2 is a substituted or unsubstituted radical carboxyalkyl, in particular C2-6 carboxyalkyl, carboxyalkenyl, in particular C2-6 carboxyalkenyl, carboxyaryl, in particular C7-13 carboxyaryl, or carboxyheteroaryl, in particular C7-13 carboxyheteroaryl; more preferably a carboxyalkyl, in particular C2-6 carboxyalkyl or carboxyaryl, in particular C7-13 carboxyaryl, optionally substituted with 1, 2, 3, 4, or 5 halogen(s), e.g. F, Cl, Br, or I, —O—R4, wherein R3 preferably has the meaning C1-6 alkyl, or two substituents, preferably adjacent substituents, taken together form a 3, 4, 5, 6 or 7 or 8 membered ring, optionally with 1, 2, 3 or 4 hetero atoms, e.g. N, O, or S; in particular preferred embodiments R1 is a C7 carboxyaryl, e.g. benzo-carbonyl, optionally substituted with halogen, e.g. F, Cl, Br or I, —O—R4 or two substituents taken together form a 5, 6 or 7 membered ring, preferably comprising 1 or 2 hetero atoms, e.g. O, N or S, preferably in this case and the preceding preferred embodiments R2 is hydrogen. It is even more preferred, that the C7 carboxyaryl is selected from the group consisting of monohalogen substituted benzo-carbonyl, in particular 1-fluoro-benzo-4-carbonyl or 1-chloro-benzo-4-carbonyl, mono substituted alkoxy-benzo-carbony, in particular 1-methoxy-benzo-carbonyl, benzo-carbonyl or benzo[1,3]dioxole-5-carbonyl.
Also more preferred is a radiohalogenated benzamide derivative of this invention, whereby X1 is an —O—R3, wherein R3 is preferably C1-10 alkyl, e.g. C1, C2, C3, C4, C5, C6, C7, C8, C9, or C10, alkyl, in particular methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, pentyl, hexyl, heptyl, C2-10 alkenyl, e.g. C2, C3, C4, C5, C6, C7, C8, C9, or C10, alkenyl, in particular ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, in particular a —O—CH3, —O—C2H5, —O—C2H5—O—CH3 group, X4 is a halogen, in particular [123] iodine, [125] iodine or [131] iodine, and X3 is a radical —NR1R2, in which R1 is substituted or unsubstituted carboxyalkyl, in particular C2-6 carboxyalkyl, carboxyalkenyl, in particular C2-6 carboxyalkenyl, carboxy aryl, in particular, C7-13 carboxyaryl, or carboxyheteroaryl, in particular C7-C13 carboxy heteroaryl, in particular an aryl-carboxylic acid group and R2 is a hydrogen. In a particular preferred embodiment X1 can be an —O—CH3 group, X4 is a halogen, in particular [123] iodine, [125] iodine or [131] iodine, and X3 is a radical —NR1R2, in which R1 is a benzo[1,3]dioxole-5-carbonyl group, a substituted or unsubstituted benzo-carbonyl group, a 1-chloro-benzo-4-carbonyl group, a 1-methoxy-benzo-4-carbonyl group, or a 1-fluoro-benzo-4-carbonyl group, and R2 is a hydrogen.
In an alternative preferred embodiment X1 can be an —O—C2H5 group, X4 is a halogen, in particular [123] iodine, [125] iodine, or [131] iodine, and X3 is a radical —NR1R2, in which R1 is substituted or unsubstituted carboxyalkyl, in particular C2-6 caiboxyalkyl, carboxyalkenyl, in particular C2-6 carboxyalkenyl, carboxyaryl, in particular, C7-13 carboxyaryl, in particular a benzo[1,3]dioxole-5-carbonyl group, a substituted or unsubstituted benzo-carbonyl group, a 1-chloro-benzo-4-carbonyl group, a 1-methody-benzo-4-carbonyl group, or a 1-fluoro-benzo-4-carbonyl group, or carboxyheteroaryl, in particular C7-C13 carboxy heteroaryl, and R2 is a hydrogen.
In an alternative preferred embodiment X1 can be an —O—C2H5—O—CH3 group, X4 can be [123] iodine, [125] iodine or [131] iodine, and X3 can be a radical —NR1R2, in which R1 is a benzo[1,3]dioxole-5-carbonyl group, a substituted or unsubstituted benzo-carbonyl group, a 1-chloro-benzo-4-carbonyl group, a 1-methoxy-benzo-4-carbonyl group, or a 1-fluoro-benzo-4-carbonyl group, and R2 is a hydrogen.
As an alternative, X1 can be an —O—C2H5—OH group, X4 can be [123] iodine, [125] iodine, or [131] iodine, and X3 can be a radical —NR1R2, in which R1 is a substituted or unsubstituted carboxyalkyl, in particular C2-6 carboxyalkyl, carboxyalkenyl, in particular C2-6 carboxyalkenyl, carboxy aryl, in particular, C7-13 carboxyaryl, in particular benzo[1,3]dioxole-5-carbonyl group, or a substituted or unsubstituted benzo-carbonyl group, a 1-chloro-benzo-4-carbonyl group, a 1-methoxy-benzo-4-carbonyl group, or a 1-fluoro-benzo-4-carbonyl group, carboxyheteroaryl, in particular C7-C13 carboxy heteroaryl, and R2 is a hydrogen. It is particularly preferred that in this context X6 is an oxygen. It is in this context also preferred that X2 and X5 are hydrogen.
Likewise preferred is a radiohalogenated benzamide derivative of this invention, whereby at least one of radicals X1 to X5 is a radical —NR1R2, whereby R1 is a carboxyalkyl group, and R2 is a hydrogen, and one of radicals X1 to X5 is an —O—R3 group, X6 is an ═NH group, and one of radicals X1 to X5 is a halogen, in particular [123] iodine, [125] iodine or [131] iodine.
Also preferred is a radiohalogenated benzamide derivative of this invention, whereby at least one of radicals X1 to X5 is a radical —NR1R2, whereby R1 is a carboxyalkyl group, and R2 is a hydrogen, and one of radicals X1 to X5 represents an —O—CH3 group, X6 represents an ═NH group, and one of radicals X1 to X5 represents a halogen, in particular [123] iodine, [125] iodine or [131] iodine.
According to a particularly preferred aspect of this invention, a radiohalogenated benzamide derivative of this invention of Formula IIa.
and pharmaceutical acceptable salts thereof are made available.According to another particularly preferred aspect of this invention, further radiohalogenated benzamide derivatives of this invention of Formula IIb to e and pharmaceutical acceptable salts thereof are made available.

Another aspect of this invention relates to a process for the production of a pharmaceutical composition for the diagnosis or treatment of tumors, in particular malignant melanoma, including the mixing of a radiohalogenated benzamide derivative of this invention with a suitable pharmaceutical vehicle. These vehicles can be selected from phosphate-buffered physiological common salt solution, physiological common salt solution, water, mixtures that consist of the previously named solutions/solvents with ethanol, dimethyl sulfoxide, Tween®, meglumine, etc.
Preferred is a pharmaceutical composition of this invention, whereby the halogen isotope is selected from F-18, Br-75, I-123, I-124, I-125, I-131 or At-211.
More preferred is a pharmaceutical composition of this invention, whereby the halogen isotope is [I-131] iodine, whose specific activity is between 10 mCi/mg and 1500 mCi/mg (non HPLC purified), preferably between 100 mCi/mg and 800 mCi/mg (non HPLC purified). If the compound is purified by HPLC or alike methods, the specific radioactivity will be determined by the specific activity of the isotope batch used and will be higher.
Still another aspect of this invention then relates to the use of a radiohalogenated benzamide derivative of this invention for the production of a preparation for the diagnosis and treatment of tumors, in particular melanomas. In this case, the compound can be used either with a diagnostically relevant radioisotope such as I-123 for a Single Photon Emission Computed Tomography (SPECT) study or with F-18/I-124/Br-76-labeled benzamide derivative for the PET. For a therapeutic application, the benzamide derivative can be labeled with I-131/I-125/At-211 and can be used for systemic radiotherapy as well as for local, intratumoral therapy.
In this case, I-131-labeled benzamide represents a special case, since both the β′-radiation portion can be used therapeutically and the accompanying γ-emission can be used diagnostically (SPECT). An advantage of the halogen-labeled compounds could consequently exist in the development of a compound with an isotope, in which a low dosage is used for diagnostic imaging and then after dosimetric tolerance calculation, a therapeutically relevant, higher radioactive dose is administered.
Within the scope of this invention, “alkyl” is defined in each case as a straight-chain or branched alkyl radical, such as, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl or hexyl, heptyl, octyl, nonyl, decyl, undecyl, or dodecyl.
Within the scope of this invention, “alkoxy” is defined in each case as a straight-chain or branched alkoxy radical, such as, for example, methyloxy, ethyloxy, propyloxy, isopropyloxy, butyloxy, isobutyloxy, sec-butyloxy, pentyloxy, isopentyloxy, hexyloxy, heptyloxy, octyloxy, nonyloxy, decyloxy, undecyloxy or dodecyloxy.
Within the scope of this invention, “cycloalkyl” is defined as monocyclic alkyl rings, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, cyclooctyl, cyclononyl or cyclododecyl, but also bicyclic rings.
Within the scope of this invention, “cycloalkenyl” is defined as monocyclic alkenyl rings, such as cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl or cycloheptenyl, cyclooctenyl, cyclononenyl or cyclodecenyl, but also bicyclic rings.
Within the scope of this invention, “halogen” is defined in each case as fluorine, chlorine, bromine, or iodine. “Radiohalogen” is defined in each case as F-18, Br-75, I-123, I-124, I-125, I-131 or At-211.
Within the scope of this invention, “alkenyl” is defined in each case as a straight-chain or branched alkenyl radical, which contains 2-6, preferably 2-4 C atoms. For example, the following radicals can be mentioned: vinyl, propen-1-yl, propen-2-yl, but-1-en-1-yl, but-1-en-2-yl, but-2-en-1-yl, but-2-en-2-yl, 2-methyl-prop-2-en-1-yl, 2-methyl-prop-1-en-1-yl, but-1-en-3-yl, but-3-en-1-yl and allyl.
The aryl radical comprises 3-12 carbon atoms in each case and can be benzocondensed in each case and/or further substituted. For example, there can be mentioned: phenyl, naphthyl, biphenyl, fluorenyl, anthracenyl, benzo[1,3]dioxole etc.
The heteroaryl radical comprises 3-16 ring atoms in each case, and, instead of carbon, can contain in the ring one or more heteroatoms that are the same or different, such as oxygen, nitrogen or sulfur, and can be monocyclic, bicyclic or tricyclic, and in addition can be benzocondensed in each case and/or further substituted.
There can be mentioned, for example, thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, etc., and benzo derivatives thereof, such as, e.g., benzofuranyl, benzothienyl, benzoxazolyl, benzimidazolyl, indazolyl, indolyl, isoindolyl, etc.; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc., and benzo derivatives thereof, such as, e.g., quinolyl, isoquinolyl, etc.; or azocinyl, indolizinyl, purinyl, etc., and benzo derivatives thereof; or quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, napththyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, xanthenyl, oxepinyl, etc.
If an acid group is included, the physiologically compatible salts of organic and inorganic bases are suitable as salts, such as, for example, the readily soluble alkali and alkaline-earth salts, as well as N-methyl-glucamine, dimethyl-glucamine, ethyl glucamine, lysine, 1,6-hexadiamine, ethanolamine, glucosamine, sarcosine, serinol, tris-hydroxy-methyl-amino-methane, aminopropanediol, Sovak Base, 1-amino-2,3,4-butane-triol.
If a basic group is included, the physiologically compatible salts of organic and inorganic acids are suitable, such as hydrochloric acid, sulfuric acid, phosphoric acid, citric acid, tartaric acid, fumaric acid, etc.
The compounds of general formula I according to the invention also contain possible tautomeric forms and comprise the E- or Z-isomers, or, if a chiral center is present, also the racemates and enantiomers.
The production of the compounds according to the invention can be carried out by a compound of formula III,
in which R12 means hydrogen or low-alkyl, optionally esterified, etherified, amidated, the nitro group reduced, acylated and radiohalogenated, whereby the radiohalogenation is carried out virtually in one of the last stages, if possible in the last stage. However, a compound of formula IV
in which R12 means hydrogen or low-alkyl, can also be nitrated and then the process is continued as described above. Another possibility consists in a compound of formula V
in which R12 means hydrogen or low-alkyl, and FG means iodine, bromine, o-triflate, O-mesylate, O-toosylate or O-nonaflate, optionally esterified or amidated, etherified, carbonylated, nitrated, and then further processed as described above.
In the production of the compounds according to the invention, the amide formation is carried out according to methods that are known in the literature. A start can be made for amide formation from a corresponding ester. According to J. Org. Chem. 1995, 8414, the ester is reacted with, e.g., aluminum trimethyl and the corresponding amine in the solvents, such as toluene, at temperatures of 60° C. up to the boiling point of the solvent. If the molecule contains two ester groups, both are converted into the same amide.
For amide formation, however, all processes that are known from peptide chemistry are available. For example, the corresponding acid in aprotic, polar solvents, such as, for example, dimethylformamide, can be reacted with the amine via an activated acid derivative that can be obtained with, for example, hydroxybenzotriazole and a carbodiimide, such as, for example, diisopropylcarbodiimide or else with preformed reagents, such as, for example, HATU (Chem. Comm. 1994, 201) or BTU, at temperatures of between 0° C. and the boiling point of the solvent. For the amide formation, the process can also be used with the mixed acid anhydride, the acid chloride, the imidazolide or the azide. In reactions of acid chloride, dimethylacetamide can be used as a solvent at temperatures from room temperature up to the boiling point of the solvent, preferably at 80-100° C. The reaction, however, can also be performed in inert solvents, such as methylene chloride or tetrahydrofuran, with the addition of a base, such as, for example, triethylamine at temperatures of −10° C. up to the boiling point of the solvent. An addition of dimethylaminopyridine has frequently proven useful.
An acylation with acid anhydrides or acid chlorides frequently leads to bisacyl compounds that can be converted by treatment with bases, such as, for example, potassium hydroxide solution or potassium carbonate, into the monoacyl compounds. The same holds true for sulfonic acid chlorides. With acid anhydrides, a bisacylation by using acid anhydride in glacial acetic acid can be avoided.
If various amide groups are to be introduced into the molecule, for example, the second ester group must be introduced after the production of the first amide group in the molecule and then amidated, or there is a molecule in which one group is present as ester and the other is present as acid, and the two groups are amidated in succession according to various methods.
An esterification of acids is possible by reaction with trimethylsilyldiazomethane. The methyl ester is then obtained. The reaction is possible in solvents such as methanol or toluene, preferably in mixtures thereof. The temperature shifts between 0° C. and the boiling point of the solvent, and is preferably room temperature. An esterification of a carboxylic acid in addition to a phenol is also possible with alcoholic hydrochloric acid, preferably at the boiling point of the solvent.
The introduction of non-radiohalogens is carried out according to processes that are known in the literature, e.g., by reaction with bromine, N-bromine or N-chlorosuccinimide or urotropin hydrotribromide in polar solvents, such as tetrahydrofuran, acetonitrile, methylene chloride, glacial acetic acid or dimethylformamide.
The reduction of the nitro group is performed in polar solvents at room temperature or elevated temperature. As catalysts for the reduction, metals such as Raney nickel or noble-metal catalysts such as palladium or platinum, or else palladium hydroxide optionally on vehicles are suitable. Instead of hydrogen, for example, ammonium formate, cylcohexene or hydrazine can also be used in a known way. Reducing agents such as tin(II) chloride or titanium(III) chloride can also be used, such as complex metal hydrides optionally in the presence of heavy metal salts. As reducing agents, iron can also be used. The reaction is then performed in the presence of an acid, such as, e.g., acetic acid or ammonium chloride, optionally with the addition of a solvent, such as, for example, water, methanol, iron/ammonia, etc. In the case of extended reaction time, in this variant, an acylation of the amino group can occur.
If an alkylation of an amino group is desired, the amine can be subjected to a reductive alkylation with aldehydes or ketones, whereby it can be reacted in the presence of a reducing agent, such as, for example, sodium cyanoborohydride, in a suitable inert solvent, such as, for example, ethanol, at temperatures of 0° C. up to the boiling point of the solvent. If a start is made from a primary amino group, the reaction can optionally be performed in succession with two different carbonyl compounds, whereby mixed derivatives are obtained [literature, e.g., Verardo et al. Synthesis (1993), 121; Synthesis (1991), 447; Kawaguchi, Synthesis (1985), 701; Micovic et al. Synthesis (1991), 1043].
It may be advantageous to form the Schiff base first by reaction of the aldehyde with the amine in solvents such as ethanol or methanol, optionally with the addition of adjuvants such as glacial acetic acid, and then to add only reducing agents, such as, e.g., sodium cyanoborohydride.
The introduction of the alkenyl group is carried out with the corresponding vinyl compounds under the conditions of the Heck reaction. For the introduction of the ethinyl groups, the Sonogashira reaction is used, and for the introduction of the aryl or hetaryl radicals, the Suzuki reaction or the Still reaction is used.
As leaving groups, halogens such as fluorine, chlorine, bromine, iodine or O-mesylate, O-tosylate, O-triflate or O-nonaflate are suitable. The nucleophilic substitution for the introduction of ethinyl radicals or ethenyl radicals is performed under catalysis of transition metal complexes, such as Pd(O), e.g., palladium tetrakistriphenylphosphine, Pd2(dba)3 or Pd(2+), such as palladium-bis-tri-o-tolylphosphine-dichloride, nickel(II) or nickel(0) according to methods that are known in the literature optionally in the presence of a base and optionally under co-catalysis of a salt, such as, for example, copper(I) iodide or lithium chloride.
As nucleophiles, for example, vinyl or ethinyl compounds, tin-organic compounds or zinc-organic compounds or boronic acids are suitable. The reaction can be performed in polar solvents such as dimethylformamide, dimethylacetamide, N-methylpyrrolidone, acetonitrile, in hydrocarbons such as toluene or in ethers such as tetrahydrofuran, dimethoxyethane or diethyl ether. As bases, inorganic bases such as alkali- or earth-alkali hydroxides or -bicarbonates, -carbonates, or -phosphates, or organic bases such as cyclic, alicyclic and aromatic amines, such as pyridine, triethylamine, DBU or Hünig base, are suitable, whereby in many cases, bases such as diethylamine or piperidine can also be solvents at the same time. The application of pressure may be necessary for the reaction. An addition of ligands, such as, for example, triphenylphosphine or xanthphos, can have a positive effect.
The substitution of leaving groups in aromatic compounds or heteroaromatic compounds by amides is carried out under catalysis, for example by palladium or copper catalysis. In the case of copper catalysis (literature, see Synlett. 2002, 427), solvents such as dioxane or dimethylformamide are used at temperatures up to the boiling point of the solvent, preferably 120° C. As a base, potassium phosphate or else cesium carbonate is used. Ethylenediamine is advantageous for complexing the copper(I) iodide that is used as a catalyst. An application of pressure is not harmful. In the case of palladium catalysis, both palladium(II) salts, such as palladium(II) acetate, and palladium(0) complexes, such as palladium (O)2dibenzylidene acetone3 (literature, see JACS 2002, 6043, THL 1999, 2035, Org. Lett 2001, 2539, THL 2001, 4381 or THL 2001, 3681), can. As solvents, toluene, dioxane or dimethylformamide are used at temperatures from room temperature up to the boiling point of the solvent, preferably around 100° C. As a co-ligand, BINAP, DPPF or xanthphos is used. A base is also necessary. For this purpose, cesium carbonate, potassium phosphate or else sodium-t-butylate is used. These components can be combined in various ways.
The amide group can also be introduced by carbonylation, however. To this end, a start is made from the corresponding aromatic or heteroaromatic compounds with a leaving group (see above), which are reacted with carbon monoxide at normal pressure or else elevated pressure and an amine in the presence of transition metal catalysts, such as, for example, palladium(II) chloride or palladium(II) acetate, palladium tetrakistriphenylphosphine or in solvents, such as, for example, dimethylformamide. The addition of a ligand such as triphenylphosphine, and the addition of a base such as tributylamine may be advantageous (see, for example, J. org. Chem. 1974, 3327; J. org. Chem. 1996, 7482; Synth. Comm. 1997, 367; Tetr. Lett. 1998, 2835, J. org. Chem. 2003, 3558).
If various amide groups are to be introduced into the molecule, for example, the second ester group must be introduced into the molecule after the first amide group is produced and then amidated, or there is a molecule in which one group is present as an ester and the other is present as an acid, and the two groups are amidated in succession according to various methods.
Acid groups can also be introduced by carbonylation, however. To this end, a start is made from the corresponding aromatic or heteroaromatic compounds with a leaving group (see above), which are reacted with carbon monoxide at normal pressure or else elevated pressure in the presence of transition metal catalysts, such as, for example, palladium(II) chloride or palladium(II) acetate, palladium tetrakistriphenylphosphine, in solvents such as, for example, dimethylformamide, whereby water is added. A base such as, for example, triethylamine is necessary. In addition, ligands, such as, for example, triphenylphosphine or preferably (1,1′-bisphenylphosphino)ferrocene, are necessary. The pressure extends from room temperature to 50 bar, preferably 5-40 bar. The reaction can prolong an elevated temperature. It extends from room temperature up to the boiling point of the solvent, and preferably a temperature of 40-80° C. is used.
An alkylation of a phenol is possible by reaction with an alkylating agent such as, for example, alkyl halide, alkyl triflate, alkyl mesylate or alkyl tosylate in solvents such as dimethylformamide, N-methylpyrrolidone, or tetrahydrofuran in the presence of bases such as cesium carbonate, potassium carbonate or else DBU, DABCO. The phenolate can also be preformed, however, by the phenol being pretreated with bases such as sodium hydride at temperatures of 0-100° C., preferably at 50° C., and then the alkylating agent being added.
Alkylation can thus be achieved in that according to the Mitsunobu variant, reaction is done with an alcohol in the presence of, for example, triphenylphosphine and azodicarboxylic acid ester.
The hydrogenation of alkene or alkine groups in the molecule is carried out in the usual way by, for example, catalytically activated hydrogen. As catalysts, heavy metals, such as palladium or platinum, optionally on a vehicle or Raney nickel, can be used. As solvents, alcohols, such as, e.g., ethanol, are suitable. The procedure is performed at temperatures of 0° C. up to the boiling point of the solvent and at pressures up to 20 bar, but preferably at room temperature and normal pressure. By the use of catalysts, such as, for example, a Lindlar catalyst, triple bonds can be partially hydrogenated to double bonds, whereby preferably the Z-form is produced. This hydrogenation is preferably performed in pyridine as a solvent with palladium on calcium carbonate as a catalyst. In the same way, the Z-double bond can be produced from the triple bond by reduction with diimine, for example according to R. M. Moriatry et al. Synth. Comm. 17, 703, 1987.
Ether cleavages are performed according to processes that are common in the literature. In this case, a selective cleavage can also be achieved in several groups that are present in the molecule. In this case, the ether is treated with, for example, boron tribromide in solvents such as dichloromethane at temperatures of between −100° C. up to the boiling point of the solvent, preferably at −78° C. It is also possible, however, to cleave the ether by sodium thiomethylate in solvents such as dimethylformamide. The temperature can be between room temperature and the boiling point of the solvent, preferably at 150° C. In the case of benzyl ethers, the cleavage is also possible with strong acids, such as, for example, trifluoroacetic acid at temperatures from room temperature up to the boiling point.
For radioiodinated compounds, in principle several methods are suitable. In particular here, the Tl/trifluoroacetic acid/NaI method, the iodate/NaI method, the use of chloroamine-T™ or Jodogen™ can be mentioned (M. Eisenhut et al., Radioiodination Chemistry and Radioiodinated Compounds, in: Handbook of Nuclear Chemistry—Vol. 4, 257-278 A. Vértes, S. Nagy and Z. Klencsár (eds.) Kluver Academic Publishers (2003)).
When the Tl/trifluoroacetic acid/NaI method is used, the benzamide precursor is dissolved under an inert gas atmosphere in trifluoroacetic acid and mixed with Tl/trifluoroacetate)3. After an incubation time, the NaI is added either in water, in dilute NaOH alkaline solution or dissolved in another suitable solvent. After stirring at room temperature or at an elevated temperature, the reaction of the precursor to form the desired product of general formula I results.
For radioiodination by the iodate/NaI method, the iodination precursor is dissolved in acid (preferably 1N hydrochloric acid), mixed with KIO3 solution (preferably aqueous), and after the halide solution of the corresponding isotope is added at room temperature, it is reacted. The reaction is then suppressed by adding, for example, Na2S2O5. The purification of the products that are produced can be carried out via normal-phase or reverse-phase chromatography.
The cleavage of the protective groups is carried out in a way that is known in the literature. Thus, a t-butyloxcarbonyl group can be removed by being reacted in a solvent such as tetrahydrofuran, dioxane or ethanol with an acid, such as, e.g., 1N hydrochloric acid at temperatures of between room temperature and the boiling point of the solvent. It is also possible to cleave the t-BOC group with strong acids such as trifluoroacetic acid at temperatures of between −20° C. and the boiling point, preferably at room temperature. A solvent such as methylene chloride is not absolutely necessary but may be advantageous. In the same way, t-butyl ester can be cleaved.
The reduction of a ketone takes place in a known way by a complex metal hydride, such as, for example, sodium borohydride or lithium borohydride, in solvents such as ethanol, tetrahydrofuran or diethyl ether at temperatures of 0° C. up to the boiling point of the solvent.
According to commonly used methods, such as, for example, crystallization, any form of chromatography or salt formation, the isomer mixtures can be separated into enantiomers or E/Z isomers.
The production of salts is carried out in the usual way, by a solution of the compound of formula I being mixed with the equivalent amount or an excess of a base or acid, which optionally is in solution, and the precipitate being separated or the solution being worked up in the usual way.
The invention is now to be further described below in the examples without being limited thereto.
Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. The following preferred specific embodiments are, therefore, to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever.
In the foregoing and in the following examples, all temperatures are set forth uncorrected in degrees Celsius and, all parts and percentages are by weight, unless otherwise indicated.